We plan to continue studies of the nitrogen metabolism of nervous tissue directed to specific problems related to the effects of naturally occurring amino acids and related substances on neuronal excitability and synaptic transmission as well as to their roles in general metabolism and maintenance in nervous tissue in health and disease. This project is concerned with the role of the gamma-aminobutyric acid (GABA) system in the central nervous system function. We are attempting to obtain answers in some of the following areas as suitable tools become available: (a) formation and metabolism of GABA in the nervous system; properties and control mechanisms of the glutamic decarboxylase and GABA transaminase systems; (b) evidence for the presynaptic release of GABA; (c) mechanism of action of GABA on membranes; (d) consideration of the transport into intracellular sites as the major mode of the removal of GABA from the synaptic cleft; (e) study of antagonists of the depressant action of GABA and the membrane changes produced by it; (f) role of the GABA system in cerebellum; (g) the role of GABA in the retina and other vertebrate neuronal systems. A plan is being made to test the idea that there may be primary defect in the GABA system in individuals with a susceptibility to schizophrenia. Studies are being made of imidazole acetic acid (IMA), a naturally occurring metabolite of histidine, since our finding of some remarkable pharmacological effects of this latter substance. The possibility is being investigated that IMA may be an inhibitory transmitter in the vertebrate CNS. Work also is in progress that is testing the possibility that the carbon chain of that portion of neuronal glutamic acid that may be employed as an excitatory transmitter may not arise chiefly from glucose via alpha- ketoglutarate, but rather from arginine, proline, histidine or other precursors by different metabolic pathways. We are continuing investigation of CNS tissue of mice with hereditary neurological disorders and beginning work with tissue from mouse strains that are normal neurologically but differ behaviorally.